1-(p-trifluoromethoxyphenyl)-biguanide

ABSTRACT

1-Aryl and aralkyl biguanides and their acid addition salts in suitable pharmaceutical dosage form are useful in the treatment of gastrointestinal disorders.

United States Patent 1 Diamond et al.

[ 5] Jan. 14, 1975 l-(P-TRIFLUOROMETHOXYPHENYL)- BIGUANIDE [75] Inventors: Julius Diamond, Lafayette Hill;

William J. Novick, Jr., Gwynedd, both of Pa.

[73] Assignee: William H. Rorer Inc., Fort Washington, Pa.

22 Filed: Feb. 12,1974

21 App1.No.:441,907

Related US. Application Data [62] Division of Ser. No. 15,967, March 2, 1970.

[52] US. Cl. 260/565, 260/295.5 S, 260/343.7,

S, 260/556 AR, 260/556 B, 260/558 A,

Primary Examiner-Leon Zitver Assistant Examiner-Gerald A. Schwartz Attorney, Agent, or Firm-Erich -M. H. Raddc [57] ABSTRACT l-Aryl and aralkyl biguanides and their acid addition salts in suitable pharmaceutical dosage form are useful in the treatment of gastrointestinal disorders.

' 1 Claim, N0 Drawings 1-(P-TRIFLUOROMETHOXYPHENYL)- BIGU ONIDE This is a division, of application Ser. No. 15,967 filed Mar. 2, 1970.

BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to pharmaceutical compositions and more particularly to pharmaceutical compositions useful as gastric antisecretory and spasmolytic agents, and to a method of using such compositions in therapy as gastric antisecretory and spasmolytic agents, i.e. to significantly reduce the volume and the acidity of the gastric fluid in humans and mammals.

2. Description of the Prior Art Many l-arylbiguanides and their simple acid addition salts are known. They are prepared, for instance, by reacting a corresponding arylamine hydrochloride and cyanoguanidine. For instance, SEYMOUR L. Sl-lA- PIRO et al. J. Am. Chem. Soc. vol. 81, p. 3725 (1959) prepared numerous l-arylbiguanides, including 1-(m-trifluoromethylphenyl) biguanide monohydrochloride. These compounds were examined for hypoglycemic activity, but they were found to be essentially devoid of this property.

BLAINE M. SUTTON, U.S. Pat. No. 2,934,535 (1960), synthesized l(p-trifluoromethylphenyl) biguanide; 1-(o-trifluoromethylphenyl) biguanide; l-(m-trifluoromethylphenyl) biguanide; and l-(trifluoromethylphenyl) biguanide hydrochloride. These compounds were employed as chemical intermediates but not as therapeutic agents.

NI-IUYEN P. BUU-l-IOI et al. C. R. Acad. Sc. Paris vol. 265, p. 930 (1967) synthesized a few I- arylbiguanides including l-(rn-trifluoromethylphenyl)- biguanide and its hydrochloride. The latter compound was found to possess significant anorexigenic activity.

However, none of these and other references or patents discloses the use of compositions containing.

l-(trifluoromethylphenyl) biguanides or other 1- arylbiguanides or l-aralkylbiguanides or their acid addition salts as gastric antisecretory and spasmolytic agents in the treatment of certain gastrointestinal diseases such as duodenal ulcer and peptic ulcer.

l-Arylkyl biguanides and l-arylbiguanides have heretofore been used or proposed for use as antidiabetics, anorexigenic, or antimalarial agents.

The pharmaceutical compositions administered heretofore as gastric antisecretory and spasmolytic drugs contain, for instance, as active agents, atropine, homatropine, propantneline bromide, dicyclomine hydrochloride, and other compounds not structurally related to l-arylbiguanides or l-aralkylbiguanides. Due to the anticholinergic properties of these compounds they are known to produce undesired side-effects such as mydriasis, xerostomia, cyclopegia, and others.

Many attempts have been made to overcome these disadvantages of the known drugs for ulcer treatment, but without any noteworthy success.

2 SUMMARY OF THE INVENTION It is one object of the present invention to provide valuable pharmaceutical compositions which contain, as active gastric antisecretory and spasmolytic agents, l-phenyl-biguanides or l-phenyl lower alkyl biguanides which are substituted in the phenyl ring, or their pharmaceutically acceptable acid addition salts, i.e., a salt of a pharmaceutically acceptable acid, said compounds being substantially free of the anticholinergic sideeffects of the heretofore used gastric antisecretory and spasmolytic agents and being of low toxicity.

Another object of the present invention is to provide a simple and effective method for treating gastrointestinal disorders and diseases, such as duodenal and peptic ulcers by the preferably oral administration of compositions containing such l-(substituted phenyl) biguanides or l-(substituted phenyl lower alkyl) biguanides or their pharmaceutically acceptable acid addition salts.

A further object of the present invention is to provide new and valuable l-(substituted phenyl) biguanides or l-(substituted phenyl lower alkyl) biguanides and their pharmaceutically acceptable acid addition salts which are useful gastric antisecretory and spasmolytic agents substantially devoid of the anticholinergic side-effects of structurally unrelated known agents of this type.

Other objects of the present invention and advantageous features thereof will become apparent as the description proceeds.

In principle, the l-substituted' biguanides which are the highly effective gastric antisecretory and spasmolytic components of the pharmaceutical compositions according to the present invention, correspond to the following formula 1 wherein X is an electron-attracting function in o-, m-, or pposition to the biguanide group, said function being, for instance, nitro, halogen (chlorine, bromine, iodine, or fluorine), cyano, sulfamoyl, methylsulfonyl, acetyl, carbomethoxy, trichloromethyl, and preferably a polyfluoro substituted group in 0- or p-position such as trifluoromethyl F C, B,B,B-trifluoroethyl F C.CH trifluoromethylsulfonyl F C.SO trifluoroacetyl F C.CO, trifluoroacetoxy F C.COO. trifluorocarbomethoxy F C.OCO-, di-(trifluoromethylamino) sulfonyl (F C) N.SO di-(trit'luoromethylamino)carbonyl (F C) N.CO, difluoromethyl F CH, B,B-difluoroethyl F CH.Cl-l a,a-difluoroethyl CH .CH di-fluoromethylsulfonyl' F CH.SO difluoroacetoxy F Cl-l.COO-, difluorocarbomethoxy F CH.OCO, di-(di-fluoromethyl- )aminosulfonyl (F CH) N.SO di-(di-fluoromethylamino)carbonyl (F Cl-l N.CO, trifluoromethoxy F CO, difluoromethoxy F CHO-, and B,B,-di-fluorovinyl F CCH;

Y is hydrogen, halogen, nitro, and trifluoromethyl;

R is hydrogen, lower alkyl with 1 to 5 carbon atoms, lower alkenyl with 2 to 5 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, phenyl, benzyl, and aand B-phenylethyl;

Alk is straight chain or branched lower alkyl with 1 to 4 carbon atoms;

HA is an acid forming with said biguanide a pharmaceutically acceptable acid addition salt, such as an inorganic acid, for instance, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, or an organic acid, for instance, methanesulfurie acid, ethanesulfuric acid, benzene sulfonic acid, toluene sulfonic acid, acetic acid, propionic acid, malic acid, succinic acid, tartaric acid, citric acid, ascorbic acid, benzoic acid, mandelic acid, nicotinic acid, glycine, alanine, glutamic acid, phthalic acid, the higher fatty acids such as stearic acid, oleic acid, or high molecular weight acids, for instance, abietic acid, and others;

m is 0 or 1;

n is 0, A, /6, 1, or 2.

The term electron-attracting function as used herein and in the claims annexed hereto indicates any atom or group which attracts electrons more strongly than hydrogen and thus is said to have a negative inductive effect (-I). Said term or the equivalent term electron-withdrawing group are explained, for instance, y

G. I. Brown, An Introduction to Electronic Theories of Organic Chemistry, Longmans, Green and Co., London, pp. 6869; by

3. S. Gould, Mechanism and Structure in Organic Chemistry, H. Holt and Co., New York (1959), pp. 207, 218; by L. F. Fieser and M. Fieser, Or-

ganic Chemistry, Reinhold Publishing Corporation, New York, (1956), p.566; by J. D..Roberts and M. C. Casserio, Basie Principles or Organic Chemistry, W. J. Benjamin, Inc, New York, (1964), PP. 802-3;

by C. R. Noller, Textbook of Organic Chemistry," W. B. Saunders Co., Philadelphia, (1958), pp. 339-341; by L. N. Ferguson, Modern Structural Theory of Organic Chemistry," Prentice Hall, lnc., Englewood Cliffs, New Jersey, (1963), pp. 412-416, and by other authors. Examples of such electron-attracting functions or groups are given by said authors. These explanations and examples are included by reference in the present application. The compounds of Formula 1 are prepared according to the processes described in the literature and patents given hereinabove on page 3 or by other known methods.

A preferred method of making such compounds consists in heating equivalent amounts of cyanoguanidine and the appropriately substituted arylamine hydrochloride or aralkylamine hydrochloride in aqueous or alcoholic systems. The reactants can also be reacted by fusing them together. The resulting hydrochloride is converted into the free biguanide by reaction with sodium hydroxide solution. The base can be converted into the desired acid addition salts by reaction with the appropriate amount of the desired acid. The reaction proceeds in principle according to the following equation:

R 201 s imicl n c mi ti m heat III 1 a 1m N 1m c m 1101 men - 3 NH NR 11 H .....(Alk) c NH c NR2 v nan a HR NH l r: c NH -l: N112 mm The l-phenylbiguanides and l-phenyl alkyl biguanides according to the present invention and their acid addition salts have been found to be highly effective urnans and ma the acidity and about \00 rn d 'c an i-(p-cyanop s \f ny p enyi) phenyh biguanit cornpou theiine, dicydo i-pheny\a\ky\biguani a o cid addition saits arec arnrnais.

- t-(p-trifl the hit m disso\utron, u

e teric coate ac, an

' Sa\ts with other rovi ed they be uncoa ce\\u\o ac may cont weetening 60 course, as

caiiy accep a TH P stance,

\ike. L'quid pre a ns ani or pepperrnin, agents su 'n and other exs rbito ca 0 o DESCRiPTiON OF E te viscosity. pharcm EMBODiMEN The preparation of new compot' n is d scribed mo procedures, 65

present inve is not \irniter 'n a sirni\a of gastroin- \owing exa p pounds are prepared suitabie rne dance art.

' e treatment 'c u\cer may d thods.

h denai or p en about rug. an

Continued Ex- Amino compound Reaction product with I ample reactant cyanoguanide 14 Z-Amino-S-fluorobenzotril-(4-Fluoro-2-trifluorofluoride hydrochloride methylphenyl) biguanide hydrochloride l5 S-Amino-Z-fluorobenzotril-(4-Fluoro-3-trifluoromefluoride hydrochloride thylphenyl) biguanide hydrochloride 16 3-Amino-4-fluorobenzotril-(2-Fluoro-54rifluorofluoride hydrochloride methylphenyl) biguanide hydrochloride l7 TArnino-kbromobenzotri- 1-(2-Bromo-5lrifluoromefluoride hydrochloride thylphenyl) biguanide hydrochloride l8 2-Amino-S-chlorobenzotril-(2-Chloro-5trifluoromefluoride hydrochloride thylphenyl) biguanide hydrochloride l9 S-Amino-Z-chlorobenzotril-(4-Chloro'3-trifluoromefluoride hydrochloride thylphenyl) biguanide hydrochloride EXAMPLE 2O EXAMPLE 31 l-(p-Trifluoromethylphenyl) biguanide methanesul fonate The biguanide base is reacted with one equivalent of methanesulfonic acid in absolute ethanol. The solvent is removed under pressure and the residue is triturated with anhydrous diethyl ether.

EXAMPLE 32 1-(p-Trifluoromethylphenyl) biguanide stearate The biguanide base is reacted with one equivalent of chloroform to yield 3.1 g. of the pure base, m.p. l95196 C. lts hydrochloride was prepared by disand introducing gaseous hy The precipitated hydrochlosolving the base in ether drogen chloride thereinto.

ride was collected.

The following comp uent R were prepared in an ana respective amino compound reacta ounds of Formula I with a substitlogous manner from the nts and cyanoguanrated with water.

EXAMPLE 33 removed under reduced pressure.

ldlne.

Exam- Amino compound Reaction product with ple No. reactant cyanoguanidine 21 3,5-Di-(trifluoromethyl)anil-(Di-3,S-trifluoromethylline hydrochloride phenyl)biguanide hydrochloride 22 p-Methylaminobenzotrifluorl-Methyll -(p-trifluoromethyl ide hydrochloride phenyl)biguanide 23 N-Phenyl-a,a,a-trifluoro-ml-PhenyLl-(m-trifluoromethyl toluidine hydrochloride phenyl) biguanide 24 N-Allyl-p-chloroaniline hyl-Allyl-l-(p-chlorophenyl) drochloride biguanide 25 N-Cyclohexyl-p-bromoaniline l-Cyclohexyl-l-(p-bromohydrochloride phenyl) biguanide 26 o-Benzylamino benzotriflul-Benzyl-l-(o trifluoromeoride hydrochloride thylphenyl) biguanide 27 N-Cyclopentyl-p-trifluoromel'Cyclopentyll -(p-trifluorothylaniline hydrochloride methylphenyl) biguanide 28 N-(p-NitrophenyU-N-(B-p enyll-B-Phenylethyl-l-(p-nitro- Acid addition salts of the bigu prepared in a manner known per se as shown, for inethyl)amine hydrochloride anide compounds are phenyl) biguanide stearic acid in absolute diethyl ether. The solvent is removed under reduced pressure and the residue is tritul-(.p-Trifluoromethylphenyl) biguanide acetate The biguanide base is reacted with o acetic acid in absolute diethyl ether and the solvent is ne equivalent of Pharmaceutical preparations as they are used in thorstance, in the following examples.

EXAMPLE 29 1-(p-Trifluoromethylphenyl) biguanide citrate apy according to the present invention are produced according to the following examples without, however, being limited thereto.

EXAMPLE 34 The biguanide base is reacted with one-third equiva- Composition; lent of citric acid in absolute ethanol. The citrate is precipitated by dilution with anhydrous diethyl ether.

150 g. of l-(p-trifluoromethylphenyl) biguanide EXAMPLE 30 hydrochloride, 3 g. of magnesium stearate, l-(p-Trlfluoromethylphenyl) biguanide hydrogen 2 g. of finely divided silica sold under the phthalate The biguanide base is reacted with one equivalent of phthalic acid in absolute ethanol. The hydrogen phthalate is precipitated by dilution with anhydrous diethyl ether.

trademark CAB-O-SlL by Godfrey l.. Cabot. lnc., Boston. Mass, and

345 g. of lactose.

The ingredients are thoroughly mixed with each othc and the mixture is filled in gelatin capsules. Each cap sule contains 500 mg. of the composition and thus 150 mg. of l-(p-trifluoromethylphenyl) biguanide hydrochloride.

EXAMPLE 35 Composition:

l g. of l-(ptrifluoromethylphenyl) biguanide nitrate,

of corn starch,

of calcium carbonate, and

of magnesium stearate.

EXAMPLE 36 Composition:

75 g. of 1-(p-trifluoromethylphenyl) biguanide,

50 g. of microcrystalline cellulose,

10 g. of polyvinylpyrrolidone,

5 g. of magnesium stearate, and

85 g. of starch. The active compound and cellulose are intimately mixed, moistened with a polyvinylpyrrolidone solution in water, and granulated by pressing through a No. sieve. The dried granules are mixed with starch and magnesium stearate and are compressed to dragee cores, each weighing 225 mg. The cores are now provided with an elastic subcoat of an aqueous sugar solution containing 60 g. of powdered acacia, 60 g. of powdered gelatin, and 600 g. of sugar per liter of solution. Thereafter a dusting powder mixture of 180 g. of powdered sugar, 60 g. of powdered starch, 1 g. of powdered talc, and l g. of powdered acacia is applied to the dragee cores. Coating with the gelatin subcoat and dusting are repeated about five times. The thus treated cores are sugar coated in the coating pan with a 60% sugar solution. Sugar coating is repeated until each dragee weighs about 400 mg.

EXAMPLE 37 Enteric Coated Tablets The tablets of example 36 are prepared by using con- :ave punches for compressing the mixture to cores and :he cores are subsequently coated with cellulose ace- :ate phthalate solution in methyl'acetate containing about 5% of diethylphthalate as plasticizer, calculated or cellulose acetate phthalate, to produce an enteric :oated tablet which is subsequently sugar-coated. Apilication of the enteric coating material is effected by praying the solution of the enteric agent onto the core urface or by pouring a concentrated solution of the eneric agent onto the tablet surface using conventional harmaceutical tablet coating techniques. The solvent l removed by heating. In place of cellulose acetate hthalate there may, of course, be used other enteric oating materials such as shellac, zein, or the like, and, required, other plasticizers.

EXAMPLE 38 OmpOSlUOIlI 50 g. of l-(p-trifluoromethylphenyl) biguanide citrate, 200 g. of dried magnesium hydroxide gel, 200 g. of dried aluminum hydroxide gel,

5 g. of magnesium stearate, 40 g. of mannitol, and 5 ml. of peppermint oil.

l-(p-Trifluoromethylphenyl) biguanide citrate, magnesium hydroxide, and aluminum hydroxide are granulated as described in Example 35, mixed with magnesium stearate, mannitol, and peppermint oil, and compressed to tablets, each weighing 500 mg.

EXAMPLE 39 Composition:

50 g. of l-(p-trifluoromethylphenyl) biguanide hydrochloride, of magnesium hydroxide gel, of aluminum hydroxide gel, of sorbitol. of methyl phydroxyhenzoate. and q.s. 5000 cc. of distilled water.

200 gv 200 g. 240 g.

The ingredients are intimately dissolved and suspended in the distilled water. Flavoring agent may be added thereto if desired. 5 cc. of the resulting suspension contain 50 mg. of l-(p'trifluoromethylphenyl) biguanide hydrochloride, 200 mg. of magnesium hydroxide, and

200 mg. of aluminum hydroxide.

EXAMPLE 40 Composition:

50 g. of l-(p-trifluoromethylphenyl) biguanide acetate.

5 g. of propyl p-hydroxyhenzoate are dissolved and diluted to 5,000 cc. with' twice distilled water after the addition of modified Sorcnsen buffer solution in an amount sufficient to adjust the pH- value to a pH of 6.0. Sodium chloride is dissolved therein in an amount sufficient to render the resulting solution isotonic. The final solution is passed through a bacteriological filter and the filtrate is autoclaved at 120 C. for l5 minutes to yield a parenterally applicable solution which contains 50 mg. of l-( p-trifluoromethylphenyl) biguanide acetate in 5 cc.

Of course, in place of l-(p-trifluoromethylphenyl) biguanide and its salts used in the above given examples, there may be employed other acid addition salts of said compound or other gastric antisecretory and spasmolytic compounds according to Formula I. Other known compounding methods and other excipients than those described hereinabove may also be used.

The amounts of active l-(substituted phenyl or phenyl alkyl) biguanide in said preparations may be varied. Solid compositions, such as tablets (uncoated, sugarcoated, enteric coated), dragees, capsules, and the like may contain between 1 mg. and 500 mg. of the active agent per dosage unit while the liquid preparations may contain between 10 mg. and mg. of said active agent per dosage unit of 5 cc. The parenterally administrable solutions contain preferably between 5 mg. and 100 mg. per 5 cc.

PHARMACOLOGICAL DATA The effect of the compounds of Formula I on gastric secretion, their spasmolytic effect, their mydriatic effect, and their toxicity were tested on animals. The results of these tests are given hereinafter:

a. Gastric Secretion Test (Rat):

Rats were fasted for 48 hours, water was given ad lib. The rats were selected at random and separated into groups of 10. The animals were treated intraduodenally (l.D.) with the test compound of the vehicle immediately subsequent to the ligation of the stomach at the pyloric sphincter (Shay rat). The animals were sacrificed with chloroform at 4 hours post-drug administration, the stomach was removed and its contents was as sayed for volume, pH, and total acids.

RESULTS Test Compound at 50 mgJkglD.

Substituent in Decrease in Gastric Decrease in b. Gastric Secretion Test (Dog):

(Handbook of Physiology, Section 6: Alimentary Canal, Volume 11: Secretion. American Physiology Society, Washington, DC, 1967.)

Female pure-bred beagles were prepared with chronic gastric fistula. Eighteen hours fasted animals were given stimulating doses of 2-deoxy-D-glucose, pentagastrin, or histamine. Gastric juice secretion was measured for 2 to 3 hours with half-hour measurements of volume, pH, and total acid. The test procedure was repeated to establish control secretions for each stimulant. Pre-treatment with 1-(p-trifluoromethylphenyl) biguanide subcutaneously reduced the volume and on Gastric Emptying in Rats, Fed. Proc. 24:714. 196- 5.)

Rats were pretreated with varying doses of 1-(ptrifluoromethyl phenyl) biguanide 30 minutes prior to the insertion of 30 AMBERLITE resin pellets (Size 16) into the stomach via a polyethylene tube. Two hours after pellet administration the rats were sacrificed and the stomachs were removed subsequent to both pyloric and esophageal ligation. The remaining pellets were counted and the percentage retention of pellets was calculated. For 1-(p-trifluoromethylphenyl) biguanide, the ED was 20 mg./kg. s.c.

e. Mydriasis Test:

(R. A. Turner, Screening Methods in Pharmacology, Academic Press, New York and London, pp. 174-175,1965.)

Ten rats per group were given the test compound at the appropriate pretreatment time and were subjected to pupillary observation with a stereoscopic microscope at 10X. Positive response of mydriasis was determined by an increase in pupil diameter over 6 units on an ocular micrometer scale. With l-(p-trifluoromethylphenyl) biguanide no mydriasis was observed at doses as high as 200 mg./kg. orally.

f. Acute Toxicity (mice):

Albino male mice (18-24 g.) were separated into groups of 10 and given the test compounds orally. Observations were made for overt toxic effects and death during a 5-day period. The LD was calculated according to the method of Litchfield-Wilcoxon. For l-(p-trifluoromethylphenyl) biguanide, the oral LD is 555 mg./kg.

total acid of gastric juice secretion. g. Acute Toxicity (Rats):

R E S U L T S Dose of Gastric Stimulant 1-(p-Trifluoromethylpheny1) biguanide 25 mg./kg. 12.5 mgjkg. 6.25 mgJkg. 3.125 mg./kg

Z-Deoxy-D-glucose X decrease total acid* 43.0 62.2 48.2 60.9

X decrease volume 0 22.4 48.5 54

Pentagastrin X decrease total acid 57.5 64.3 27.8

X decrease volume 0 0 0 Histamine X decrease total acid 26.5 53.6 27.2

X decrease volume Average of four dogs per dose RESULTS Dose of 1-(p-trifluoromethylpheny1) Decrease in Decrease in biguanide Ulcer Grade number of ulcers 25 mgJkg. 19.2% 41.7% mgJkg. 60.3 75.0%

cl. Spasmolytic Test:

(D. A. Brodie, and S. K. Kundrats, Effect of Drugs Male Wistar rats (120-160 g.) were separated into 50 groups of 10 and were given the test compounds orally. Observations were made for overt toxic effects and death during a five-day period. The LD was calculated according to the method of Litchfield and Wilcoxon. For 1-(p-trifluoromethylphenyl) biguanide, the oral LD is 600 mg./kg.

These pharmacological data clearly prove the excellent gastric antisecretory and spasmolytic activity as well as the substantial absence of mydriatic side-effects andthe low toxicity of the claimed compounds and especially of l-(p-trifluoromethylphenyl) biguanide. 1t may be mentioned that those animal tests are accepted by the art as appropriately correlated with human util- 1ty.

Oral or parenteral administration of the compositions according to the present invention to human patients suffering from duodenal or peptic ulcers have confirmed these animal tests.

We claim: 1. 1-(p-Trifluoromethoxyphenyl) biguanide or a salt thereof of a pharmaceutically acceptable acid. 

